The objective of this proposal is to study in man the genetics of immune surveillance against virus infection at the level of cytotoxic cells by use of in vitro models whereby spontaneously transformed human derived cell lines infected with Feline Sarcoma Virus (FeSV) or Epstein Barr Virus (EBV) are used as stimulators and/or targets for a model to study natural killer (NK) activity, antibody dependent cytotoxicity (ADCC), and cell mediated cytotoxicty (CML). We propose to characterize in this context the effector cells in NK, ADCC and CML by fractionating lymphocytes into B, T, null, Tu and T gamma subsets and assay their relative contribution to each of these activities. The various effector cells, active against virally infected cells will be studied for cell surface determinants and functional characteristics that distingish them amongst each other. The importance of HLA-A,B.C and DR (Ia) antigens in NK, ADCC, CML against virus infected cells will be assessed by using a panel of fully HLA typed normal donors in conjunction with EBV transformed homozygous typing cells infected and uninfected with FeSV as sensitizers and/or targets and by the use of blocking and/or cytotoxic xeno- and alloantisera directed against HLA specificities at stimulator, effector and target cell levels. In an alternative approach, we shall do family studies whereby we shall use cells from random families, as well as cells from selected families, where one or both parents were shown to exhibit either low or high killing activity in a particular assay system. The cells from progenies will be further assayed to ascertain inheritance patterns of killing activity in relationship to selected HLA markers to ascertain the importance of immune response (Ir) genes in cytotoxicity to virus modified targets.